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Molecular Mechanisms Responsible KPC-135-Mediated Resistance to Ceftazidime-Avibactam in ST11-K47 Hypervirulent Klebsiella pneumoniae .

Abstract Ceftazidime-avibactam resistance attributable to the bla KPC-2 gene mutation is increasingly documented in clinical settings. In this study, we characterized the mechanisms leading to the development of ceftazidime-avibactam resistance in ST11-K47 hypervirulent Klebsiella pneumoniae that harbored the bla KPC-135 gene. This strain possessed fimbriae and biofilm, demonstrating pathogenicity. Compared with the wild-type KPC-2 carbapenemase, the novel KPC-135 enzyme exhibited a deletion of Glu168 and Leu169 and a 15-amino acid tandem repeat between Val262 and Ala276. The bla KPC-135 gene was located within the Tn 6296 transposon truncated by IS 26 and carried on an IncFII/IncR-type plasmid. Compared to the bla KPC-2 -positive cloned strain, only the MIC of ceftazidime increased against bla KPC-135 -positive K. pneumoniae and wasn't inhibited by avibactam (MIC 32 μg/mL), while clavulanic acid and vaborbactam demonstrated some inhibition. Kinetic parameters revealed that KPC-135 exhibited a lower Km and k cat/ Km with ceftazidime and carbapenems, and a higher (∼26-fold) 50% inhibitory concentration with avibactam compared to KPC-2. The KPC-135 enzyme exerted a detrimental effect on fitness relative to the wild-type strain. Furthermore, this strain possessed hypervirulent determinants, which included the IncHI1B/FIB plasmid with rmpA2 and expression of type 1 and 3 fimbriae. In conclusion, we reported a novel KPC variant, KPC-135, in a clinical ST11-K47 hypervirulent K. pneumoniae strain, which conferred ceftazidime-avibactam resistance, possibly through increased ceftazidime affinity and decreased avibactam susceptibility. This strain simultaneously harbored resistance and virulence genes, posing an elevated challenge in clinical treatment.

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